Division
of Radiation and Cancer Biology, Department of Radiation Oncology,
Stanford University School of Medicine, Stanford CA 94305.

Abstract

Recent
findings in the fields of oncogenic regulation of metabolism,
mitochondrial function and macromolecular synthesis have brought tumor
metabolism and the Warburg effect back into the scientific limelight. A
number of metabolic pathways that seem to be important for tumor growth
are being touted as novel targets for anti-cancer drug development. One
of the candidates in this class of drugs being investigated is
dichloroacetate, a molecule used for over 25 years in the treatment of
children with inborn errors in mitochondrial function. This pyruvate
mimetic compound stimulates mitochondrial function by inhibiting the
family of regulatory pyruvate dehydrogenase kinases (PDK1-4). The
stimulation of mitochondrial function, at the expense of glycolysis,
reverses the Warburg effect, and is thought to block the growth
advantage of highly glycolytic tumors. Interestingly, some of the recent
in vitro findings have shown very modest "anti-tumor cell activity" of
DCA when cells are treated in a dish. However, several studies have
reported "anti-tumor activity" in model tumors. This apparent paradox
raises the question, how do we evaluate cancer drugs designed to target
tumor metabolism? Traditional approaches in cancer drug development have
used in vitro assays as a first pass to evaluate potential lead
compounds. The fact that DCA has better in vivo activity than in vitro
activity suggests that there are unique aspects of solid tumor growth
and metabolism that are difficult to recapitulate in vitro, and may be
important in determining the effectiveness of this class of drugs.